tbuckley/cabot-search huggingface dataset:
QLTI-23. BRAIN TUMOR-RELATED PAIN: INNOVATIVE APPROACHES TO DIAGNOSIS, TREATMENT, AND QUALITY OF LIFE ISSUES: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Chukwuyem Ekhator, Ramin Rak, Ramya Tadipatri, Ekokobe Fonkem, Jai Grewal
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE The purpose of this systematic review and meta-analysis is to evaluate the various innovative approaches to diagnosing and treating patients presenting with brain tumor-related pain. BACKGROUND Brain tumors make up for lower than 2% of all cancers, which is heavily linked to high morbidity, deteriorated quality of life, and the death of the affected patients. Glioblastoma (GBM) makes up 38% of the malignant brain glioma.The main treatment approaches for gliomas are widely dependent on chemotherapy and radiation therapy. However, these methods have been associated with vast side effects which constitute the quality of life of the patient. METHODS This systematic review and meta-analysis conformed to PRISMA guidelines. A total of 3025 studies were assessed through the eligibility criteria to remain with twenty eligible studies. The included studies were then grouped into two categories; group one comprised 14 studies that focused on an innovative approach to diagnosis and treatment of gliomas, and six studies comprised of studies that focused on health-related quality of life (HRQoL) of patients with brain tumors. RESULTS Twenty studies that met the inclusion criteria were analyzed independently and in two groups: diagnosis and treatment and quality of life issues of brain tumor patients. In one group, one study revealed a relatively progression-free survival (PFS) going up to 57 weeks and overall survival (OS) time of more than 20 weeks after the initial surgery. Group two indicated HRQoL issues associated with symptoms such as headaches, fatigue, trauma, cognitive and personality dysfunction, leg weakness, and neurological deficits. CONCLUSION Timely diagnosis of the gliomas has significant improvements to the overall survival. Treatment approaches explored in the studies include Temozolomide (TZ), Gliadel Wafer, immunogeno-type, peptide vaccination, Bevacizumab, chemotherapy, radiation therapy, and Temsirolimus. Chemotherapy and radiation therapy have been linked to a deteriorated quality of life of the patients
SURG-42. MOLECULAR PROFILE CONSENSUS CLUSTERING DEFINES CLINICALLY DISTINCT GROUPS IN IDH WILD-TYPE GLIOBLASTOMA
Authors: Zachary Gersey, Arka Mallela, Xiaoran Zhang, Matthew Pease, Mohamed Abdelhakiem, Thomas Pearce, Frank Lieberman, Megan Mantica, Richard Phillips, Stephen Bagley, MacLean Nasrallah, Zev Binder, Steven Brem, Isaac Chen, Donald M O’Rourke, Pascal Zinn, Zaid Siddiqui, Nduka Amankulor
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVES Although the impact of surgery in glioblastoma (GBM) is well-established, there is insufficient data to determine how surgical resection affects overall survival (OS). The impact of other GBM genomic alterations on EOR-induced survival remains poorly understood. Here, we leverage a large cohort of GBM patients with genomic data to establish the impact of genomic alterations on resection-dependent overall survival in GBM. METHODS 537 IDH WT GBMs from UPMC were analyzed using Glioseq next generation sequencing panel. Using molecular profiles derived from Glioseq data, semi-supervised Monte Carlo reference-based consensus clustering was used to define 5 distinct groups. Cox Proportional Hazards models were used to identify predictors of OS within molecular groups. RESULTS Clustering of 537 IDH wild-type GBM identified 5 distinct groups: 1: TERT mutated/MGMT methylated/EGFR mutated or gain; 2: TERT mutated /MGMT methylated/p53 mutated; 3: TERT WT; 4: TERT mutated/MGMT methylated/CDKN2A loss; 5: TERT mutated/MGMT unmethylated. Thresholds in postoperative residual contrast enhancing volume (rCEV) and residual non-contrast enhancing volume (rNCEV) were identified which marked significant differences in median overall survival (MOS) between molecular groups in rCEV -Group 1: 11.7cc, Group 2: 14.4cc, Group 3: 1.1cc, Group 4: 0.1cc, and Group 5 1.1cc. Sex, age, KPS &amp;gt;70, temozolomide, and radiation along with thresholded rCEV and rNCEV were used in multivariate Cox analyses. Groups demonstrated distinct predictors of OS: radiation only in Group 1 tumors, low rCEV in Group 2 tumors, younger age, temodar, low CEV, and KPS &amp;gt;70 in Group 3 tumors, female sex, younger age, radiation, KPS &amp;gt;70 low rCEV in Group 4 tumors, and KPS &amp;gt;70, temodar, and low rCEV in Group 5 tumors. CONCLUSIONS Clustering results suggest that there are clinically distinct molecular groups of IDH wild-type glioblastomas. Age, sex, KPS &amp;gt;70, temozolomide treatment, radiation therapy, and EOR have varying affects on these molecular groups.
CNSC-08. TUMOUR-INFILTRATED CORTEX PARTICIPATES IN LARGE-SCALE COGNITIVE CIRCUITS
Authors: Ayan Mandal, Moataz Assem, Rafael Romero-Garcia, Pedro Coelho, Alexa McDonald, Emma Woodberry, Robert Morris, Stephen Price, John Duncan, Thomas Santarius, John Suckling, Michael Hart, Yaara Erez
Journal: Neuro-Oncology (2022)

Abstract In neurosurgery, tumour-infiltrated cortex is generally assumed to be non-functional. While prior studies have suggested integration of tumour-infiltrated tissue in relatively local circuits responsible for language and motor function, it is unknown whether such tissue can participate in distributed networks important for higher-order cognitive abilities like executive function. We tested the hypothesis that diffuse low-grade gliomas integrate into large-scale cognitive circuits using intracranial electrocorticography and resting-state functional magnetic resonance imaging of four patients. To identify brain areas recruited for executive function, electrocorticography recordings were acquired from tumour-infiltrated tissue under three conditions: i) baseline (rest), ii) simple counting (1-20; “easy”), and iii) switch counting (1-a-2-b-3-c etc.; “hard”). In each patient, we observed significant task-based high gamma power modulations in tumour-infiltrated cortex in response to increasing cognitive effort (p &amp;lt; 0.05), implying preserved functionality of neoplastic tissue for complex tasks. Additionally, tumour locations corresponding to task-responsive electrodes exhibited functional connectivity patterns that significantly co-localised with canonical brain networks implicated in higher-order cognitive processing (p &amp;lt; 0.05). Finally, dorsal attention network connectivity in tumour-infiltrated cortex correlated with high gamma power elevations during increased cognitive demand (χ 2(1) = 5.14; p = 0.023), establishing a concordance between both techniques. Overall, this study contributes convergent evidence that tumour-infiltrated cortex can participate in large-scale neurocognitive circuits, prompting a reconsideration of traditional notions of neoplastic brain tissue.
INNV-05. CO-OCCURRENCES OF A HIGH-GRADE GLIOMA WITH CAVERNOUS MALFORMATIONS AND PATHOGENIC VARIANTS IN PDCD10 AND SMARCA4
Authors: Sudarshawn Damodharan, Hannah Glanz, Kelcy Smith-Simmer, Jeffrey Helgager, Diane Puccetti
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION The co-occurrence of multiple disease processes can make for more challenging diagnoses. Here we report an unusual case of a patient found to have an IDH1-mutant high-grade glioma along with multiple cerebral cavernous malformations and pathogenic germline variants in PDCD10 and SMARCA4. Case Description: A 17-year-old female presented with left arm paresthesia and weakness along with persistent headaches within the frontal and occipital regions that progressed in intensity to include nausea and emesis. A fast sequence magnetic resonance imaging (MRI) of her head was obtained that revealed the presence of multiple bilateral cystic lesions suspicious for cavernomas with the most notable lesion in the right parietal lobe. Ophthalmology consultation revealed grade III papilledema bilaterally. A full brain MRI with and without contrast was obtained and demonstrated a right anterior parietal lobe lesion with associated mass effect, as well as multiple bilateral supratentorial and left cerebellar cavernous malformations. The patient underwent tumor debulking of her dominant lesion. Pathology revealed an IDH1 mutant diffuse astrocytoma, WHO grade 3. Germline genetic testing was pursued which revealed a PDCD10 pathogenic variant consistent with familial cerebral cavernous malformation syndrome and a likely pathogenic variant in SMARCA4. Treatment of her high-grade-glioma included radiation therapy followed by maintenance oral temozolomide. DISCUSSION This case illustrates the unusual co-occurrences of a high-grade glioma with familial cavernous malformation syndrome and germline pathogenic variants in PDCD10 and SMARCA4. Our patient continues to do well clinically, but because of her now significant risk of developing ovarian cancer she has elected to undergo a prophylactic bilateral salpingo-oophorectomy. Recognition of abnormal genetic results is critical in the setting of multiple disease processes and can play a crucial role in the on-going care for a patient.
NCOG-02. STEREOTACTIC RADIOSURGERY (SRS) FOR BRAIN METASTASES FROM MELANOMA: AN EVALUATION OF OUTCOMES AT A UK TERTIARY CENTRE
Authors: Puteri Abdul Haris, Omar Al-Salihi, Kirsty Blythe, Kazumi Chia, Sheila Hassan, Caroline Sisodia, Lucy Brazil
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Brain metastases (BM) are common in melanoma and historically associated with poor prognosis. Targeted systemic treatment have improved prognosis, and stereotactic radiosurgery (SRS) may offer an effective and less neurotoxic option. We evaluated the outcomes and potential prognostic factors of patients treated with SRS. METHODS Retrospective study of patients treated with linac-based SRS for BM from melanoma in a UK tertiary centre between August 2017-September 2021. Overall survival (OS), intracranial progression-free survival (IPFS), and prognostic factors were evaluated using Kaplan–Meier analysis, log-rank test, and Cox proportional-hazards model. RESULTS Median follow up was 32 months. 69 patients were included. Median age was 59 years old (range 30-93), and 63% were male. 99% had performance status of 0/1. 45% had BRAF mutation, and 68% had stable extracranial disease at SRS. 62 patients had first-line treatment with SRS. 133 BM were treated, with mean volume of 0.39 cm3(range 0.02-18.82). Median prescription dose was 23 Gy (range 14-24Gy), prescribed to 100% isodose. Median OS and IPFS from SRS was 18 months (95% CI 5-31), and 12 months (95% CI 6-18), respectively. 6 months and 1 year local control (LC) rate were 79% and 64 %, respectively. 91% had out-of-field recurrences. Patients with BRAF mutation had shorter IPFS compared to BRAF WT (7 months vs 18 months, HR 2, p=0.04). 36% were on BRAF inhibitors, and IPFS were longer for patients on immunotherapy within 3 months of SRS (15 months vs 4 months, HR 2.6, p=0.03). There was non-significant trend towards shorter OS and IPFS for patients who were male, ≥ 65 years old, BRAF mutant, progressive extracranial disease, &amp;gt; 4 BM, and total volume of ≥ 5cm3. CONCLUSION SRS demonstrates good OS and LC for treatment of BM from melanoma. Prospective studies should establish the synergistic effects between targeted treatment and SRS.
NIMG-69. MRI T2 RELAXIVITY IN THE PREDICTION OF PROGRESSION-FREE SURVIVAL IN NEWLY-DIAGNOSED GLIOBLASTOMA: WHOLE BRAIN MEASUREMENTS AND DEEP LEARNING
Authors: Aaron Rulseh, Josef Vymazal
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumour; we aimed to evaluate T2 relaxivity in their follow. Fifty-one newly diagnosed GBM followed at our department after surgery and combined chemo-radiotherapy were included (&amp;gt; 180 days progression-free survival [PFS] as determined by RANO, ≥ 3 MRI examinations in the PFS interval). All data used were prior to progression. T2 relaxation rates (1/T2f) were calculated voxel-wise assuming mono-exponential decay. Whole-brain (WB) values were extracted including skewness, kurtosis, mean, median, 15 and 85 percentile histogram values and variance. We additionally segmented the 1/T2f volumes using a 5 compartment Gaussian mixture model, producing mean, variance and percent per component. To evaluate predictive potential with respect to PFS, we used a deep long short-term memory (LSTM) model in tensorflow (4 timesteps). Twenty subjects were included in the predictive model, as inclusion criteria differed (progression, ≤ 120 days between all MRIs [mean 44.3 days], ≥ 4 PFS MRIs). Two models were tested: a regression model (days to progression) and a classification model (±18 months PFS; models differed in output layer). Both models were run 10 times; mean results are presented. We found WB median 1/T2f correlated with PFS, as values decreased prior to progression. WB median 1/T2f linear regression slopes also differed in progression vs. pseudo-progression. The deep LSTM regression model achieved an R2 of 86%. The deep LSTM classification model achieved a mean macro precision of 85%, recall 84% and F1 accuracy of 84% in classifying progression/no progression at an 18 month cutoff. We found very intriguing results with WB median 1/T2f measurements in distinguishing progression from pseudo-progression, and in suggesting progression despite otherwise unremarkable imaging. A more complex predictive model, using a fully-automated segmentation method followed by deep learning, was very promising. Our results may find utility in the monitoring of GBM patients.
PATH-17. DISTINCT MOLECULAR SUBCLASSES OF H3F3A-WILDTYPE, EGFR-ALTERED PEDIATRIC-TYPE DIFFUSE MIDLINE GLIOMAS WHO CNS GRADE 4
Authors: Erik Williams, Priscilla Brastianos, Hiroaki Wakimoto, Daniel Cahill, Sandro Santagata, Tareq Juratli
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVES Histone gene H3K27-altered diffuse midline glioma (DMG) are malignant tumors that occur in all age groups. In this study, we report comprehensive genomic profiling from H3F3A-wildtype, EGFR-altered DMG, as a distinct and newly recognized subset of pediatric-type DMG. METHODS Tumors were profiled in the comprehensive genomic profiling (CGP) program at Foundation Medicine between 2013-2020. Information from pathology reports, histopathology review, and patient clinical data was assessed. RESULTS We collected demographic and genomic data from 39 pediatric patients with H3F3A-wildtype, EGFR-altered HGG (17 females, 22 males; median age: 8.5 years, range 1-18 years). Female patients were younger at first diagnosis compared to male (median age 7 years vs. 10 years). All cases were microsatellite stable (MSS). The EGFR alterations consisted of 30 mutations and 9 amplifications. The mutations were distributed across the entire gene with no clear hotspot location. Our genomic data converged to identify three distinct molecular patterns. The first and most common group contained TP53 mutations (n = 17, 43.5%), showed no association with patient sex (8 females, 9 males), contained ATRX mutations (n = 3) and CDKN2A deletions (n = 5); these tumors did not harbor pathogenic mutations in TERTp, PIK3CA/PIK3R1, BCOR/BCORL1, STAG2, or SETD2. The second group featured TERTp-mutant tumors (n = 10), were more common in males (70%), and often demonstrated additional mutations in PIK3CA/PIK3R1 (n = 4), BCOR/BCORL1 (n = 4), CDKN2A/B (n = 4), and SETD2 (n = 2). The third group (n = 12) lacked TERTp and TP53 mutations and had a heterogeneous spectrum of non-recurrent mutations, including one CDKN2A/B deletion. CONCLUSIONS We have identified three distinct molecular subclasses that defined specific genomic tumor subgroups in pediatric-type EGFR altered DMG. Overall, these data increase our understanding of the pathobiology of this DMG subset and can guide the design of clinical trials.
TMIC-66. FIBROBLAST ACTIVATION PROTEIN: TISSUE EXPRESSION, POSITRON-EMISSION TOMOGRAPHY UPTAKE AND ITS PROGNOSTIC SIGNIFICANCE IN GLIOSARCOMAS AND GLIOBLASTOMAS
Authors: Christoph Oster, Kathy Keyvani, Tobias Blau, Teresa Schmidt, Jonas Feldheim, Lazaros Lazaridis, Christoph Kleinschnitz, Ulrich Sure, Hans-Ulrich Schildhaus, Björn Scheffler, Ken Herrmann, Sied Kebir, Martin Glas
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Although histologically distinct, gliosarcomas and glioblastomas are treated according to the same standards. Fibroblast-activation-protein (FAP) is a component of a tumor-specific subpopulation of fibroblasts that play a critical role in tumor growth and invasion. Few case studies suggest an elevated expression of FAP in glioblastoma and a particularly strong expression in gliosarcoma, possibly for its predominant mesenchymal differentiation. However, the prognostic impact of FAP in glioblastoma and gliosarcoma is unclear. Question:What is the clinical relevance of FAP-expression in gliosarcoma and glioblastoma and how does it correlate with FAPI46-PET-uptake? METHODS In a retrospective analysis, patients diagnosed with glioblastoma and gliosarcoma were enrolled. Histological examination was performed using immunohistochemical FAP-staining and quantitative analysis with standardized FAP-Score (0 to 3,with higher values indicating stronger expression). In a subset of patients, FAPI46-PETs have been performed. The SUV values are planned be correlated with FAP-expression in the tumor tissue. Data obtained from immunohistochemical analysis and SUV values are planned to be brought into perspective with clinically relevant prognostic factors, including survival estimates. RESULTS A total of 45 patients have been enrolled. On immunohistochemical staining, gliosarcomas expressed significantly more FAP (average FAP-Score,2.3) than glioblastomas (average FAP-Score,0.7,p&amp;lt; 0.0001). While in glioblastoma FAP-expression was confined to the perivascular space, in gliosarcoma the neoplastic cells themselves -in addition to the perivascular extracellular matrix- expressed FAP. Initial analyses indicate that tissue FAP-expression is correlated with tracer uptake on FAPI46-PET. Further studies on clinical relevance using correlation to clinical data are currently underway. CONCLUSIONS This study indicates that FAP-expression is much more abundant in gliosarcomas as opposed to glioblastomas. This could open not only a diagnostic but also a therapeutic gap. The prognostic role and the association of FAP-tissue expression with FAPI46-PET tracer uptake will be reported at the time of abstract presentation.
CTIM-31. IMMUNOLOGIC MONITORING AFTER ADOPTIVE CELL THERAPY IN PEDIATRIC PATIENTS WITH RECURRENT MEDULLOBLASTOMA USING IMMUNOGENOMICS APPROACH
Authors: Oleg Yegorov, Changlin Yang, Duane Mitchell
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Adoptive cellular therapy (ACT) using transfer of tumor-specific lymphocytes has emerged as a potent strategy for treatment of advanced and refractory malignancies. We have employed the use of total tumor RNA (TTRNA)-pulsed DCs in the ex vivo expansion of tumor-specific lymphocytes for use in adoptive cellular therapy targeting pediatric malignant brain tumors. METHODS Total RNA was isolated from patient PBMC samples collected prior to adoptive cellular therapy and after 2-weeks and 4-weeks following immunotherapy treatment from 18 patients (Re-MATCH protocol, FDA IND BB-14058). We applied bulk RNA-Seq and high-throughput T cell receptor sequencing to monitor changes in blood draws after ACT. RESULTS We observed an increase of expression level of genes responsible for T cell activation in PBMC after adoptive cell therapy. We found that these genes were involved in T cell signaling pathways, proliferative signals, and cytokine production. The data revealed that certain T-cells were clonally expanded after ACT, with an increasing number of “hyper-expanded” TCR clones (comprising &amp;gt; 1% of all TCR beta or alpha sequences) after adoptive cellular therapy. These TCR clones established a new balance in the peripheral blood that was stable over the month following the completion of cellular immunotherapy. Hyper-expanded TCR clones and increased TCR diversity following ACT was associated with radiographic response to ACT and prolonged progression-free and overall survival. Limited TCR expansion and diversity following ACT was observed in patients with short overall and progression-free survival. CONCLUSIONS These results emphasize the importance of gene expression profiling to achieve higher resolution in monitoring immune responses in patients receiving immunotherapeutic treatment. Also, these findings support further study of the use of TCR sequencing to monitor responses to adoptive cellular therapy and suggest that TCR clonal expansion and increasing TCR diversity following treatment may be associated with positive clinical responses.
NCOG-08. IMPACT OF IMMUNOTHERAPY ON PREVALENCE OF BRAIN METASTASES IN MALIGNANT MELANOMA: A REAL-WORLD POPULATION-LEVEL ANALYSIS
Authors: Debarati Bhanja, Angel Baroz, Caleb Stahl, Hannah Wilding, Alireza Mansouri
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Melanoma brain metastases (MBM) are often associated with poor prognosis. Over the last decade, the treatment paradigm for malignant melanoma shifted with the introduction of immunotherapies (ITs), including ipilimumab (ipi) and nivolumab (nivo). Recent clinical trials suggest that IT offers a survival benefit in MBM and may suffice as the sole intervention in those with small, asymptomatic lesions. Secondary trial analyses suggest IT may reduce rates of BM. The goal of this study was to assess the potential impact of IT in reducing prevalence of MBM in a real-world population-level analysis. METHODS A retrospective query of TriNetX, a database that collates clinical data from 92 healthcare organizations, was performed. Melanoma patients without brain metastases at diagnosis were stratified as: 1) ipi and nivo (dual-IT), 2) ipi alone (single-IT), or 3) no IT treatment (no-IT). A new diagnosis of MBM, from one month of initiating IT to any time after, was compared among cohorts. Median overall survival (OS) of MBM patients were calculated and compared using Kaplan Meier analysis and log-rank tests. RESULTS 732,555 melanoma patients were included (717,408 no IT, 4,585 dual-IT, 4,101 single-IT). Mean ages at MBM diagnosis were 66.9, 61.5, and 63.2 years, respectively. MBM prevalence was 1.5%, 9.6%, and 15.6%, for the respective cohorts (p &amp;lt; 0.0001). Dual-IT was associated with a lower rate of MBM compared to single-IT (OR [95%CI], 0.64 [0.61-0.77]). After propensity score matching for age, sex, and comorbidities, median OS were not statistically different between the no-IT, dual-IT, and single-IT cohorts (347, 400, 414 days) for MBM patients. CONCLUSION This analysis of real-world data suggests that dual-IT for malignant melanomas decreased the incidence of MBMs compared to single-IT. However, survival outcomes remain comparable once patients succumb to the MBM diagnosis. Prospective studies are underway to look at MBM prevalence given various dual-IT.